Elbasvir/grazoprevir administered for 12 weeks via percutaneous endoscopic gastrostomy tube achieves sustained virologic response: A case report and a review of the literature.

Enteral tubes are necessary for certain patients; however, medication absorption can be affected by this route of administration potentially resulting in decreased efficacy. All first-line treatments for Hepatitis C Virus (HCV) infection are only available as tablets and may have decreased absorption if administered via an enteral tube. This report describes the first case of a pegylated interferon and ribavirin treatment-experienced patient who successfully achieved HCV cure after 12 weeks of elbasvir/grazoprevir administered via percutaneous gastrostomy tube. We further review the available pharmacokinetic and clinical literature regarding administration via enteral feeding tubes for all first-line direct-acting antivirals (DAAs). The literature suggests that crushed administration can be considered for DAAs in patients with gastric access. However, caution should be exercised in patients with extragastric enteral tubes and in those with altered gastrointestinal tract anatomy.

A Pharmacokinetic/Pharmacodynamic Model to Predict Effective HIV Prophylaxis Dosing Strategies for People Who Inject Drugs.

The goal of this work was to evaluate dosing strategies for tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine (FTC) for pre-exposure prophylaxis (PrEP) with injection drug use with a pharmacokinetic/pharmacodynamics analysis of concentration data generated from two single-dose clinical studies conducted in healthy women. Population pharmacokinetic models were developed using measured intracellular metabolite, endogenous nucleotide competitors, and extracellular parent drug concentrations. Intracellular metabolite concentrations were normalized to endogenous competitors and compared with an EC90 target for PrEP efficacy. Monte Carlo simulations were used to select effective dose strategies of single agents (TAF, TDF, and FTC) and combinations (TDF + FTC and TAF + FTC). Daily, intermittent, and event-driven dosing regimens at varying dosage amounts were explored. When combined, TDF + FTC and TAF + FTC both provided quick (0.5 hours) and durable (up to 84 and 108 hours, respectively) protection of ≥99% after a single dose. When dosed twice per week, protection remained at 100%. Single-agent regimens provided lower estimates of protection than either combination tested. Here, the application of pharmacokinetic modeling to in vitro target concentrations demonstrates the added utility of including FTC in a successful PrEP regimen. While no TAF-based PrEP data are currently available for comparison, this analysis suggests TAF + FTC could completely protect against percutaneous exposure with as little as two doses per week.

Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV-Infected Patient Following Oral and Jejunostomy-Tube Administration.

The use of enteral feeding tubes to administer antiretroviral medications is necessary in certain patients with human immunodeficiency virus (HIV) infection. However, adequacy of drug exposures after these administration routes are largely unknown, making dosing recommendations and the attainment of viral suppression challenging in this patient population. This report describes a patient with advanced HIV infection and a complicated medical history including long-term intractable nausea/vomiting necessitating antiretroviral medication administration via a Roux-en-Y jejunostomy (J)-tube. Pharmacokinetic assessments were performed to compare differences in antiretroviral drug absorption and plasma exposure following oral and J-tube administration of dolutegravir, tenofovir disoproxil fumarate, and emtricitabine. Results were also compared with published pharmacokinetic data in HIV-infected individuals. Exposure to dolutegravir and tenofovir were similar between J-tube and oral administration routes, whereas emtricitabine exposure was 38% lower when administered via J-tube. However, in comparison with reference data in HIV-infected individuals taking these medications orally, exposure to dolutegravir and tenofovir was 75-76% and 55-61% lower, respectively, following both routes of administration. Emtricitabine exposure was similar to and 71% higher than reference data following J-tube and oral administration, respectively. This report highlights the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral treatment success.

Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues.

Objectives: Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide's mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues. Methods: Healthy seronegative women were given 5, 10 or 25 mg of tenofovir alafenamide ( n = 8/group). Each participant provided plasma, PBMC and cervical, vaginal and rectal tissue samples over 14 days. Plasma, cell lysate and tissue homogenate concentrations were analysed by LC-MS/MS. Dose proportionality was declared in plasma and PBMCs if the natural log AUC versus natural log dose regression line 90% CI was within 0.57-1.43. In vitro tenofovir-dp formation was assessed in PBMCs and ectocervical (Ect1/E6E7) and vaginal (VK2/E6E7) cells incubated in 0.5 and 10 µM tenofovir alafenamide or tenofovir. clinicaltrials.gov: NCT02357602. Results: Following single doses of 5, 10 and 25 mg, median (IQR) tenofovir plasma AUC 0-14 days was 52.8 (49.5-59.6), 78.1 (68.2-86.9) and 169.7 (131.2-211.4) ng·h/mL and tenofovir-dp PBMC AUC 0-14 days was 2268 (1519-4090), 4584 (3113-5734) and 9306 (6891-10785) fmol·h/10 6 cells, respectively. Tenofovir was quantifiable in 52% and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 19% of FGT and GI tissues, respectively. Plasma tenofovir and PBMC tenofovir-dp were dose proportional (90% CI = 0.87-1.15 and 0.62-1.02, respectively). In vitro tenofovir-dp was 1.7-17-fold higher in epithelial cells than PBMCs. Conclusions: After tenofovir alafenamide dosing in vivo , tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro . These findings warrant further investigation of tenofovir alafenamide's pharmacology.

Predicting HIV Pre-exposure Prophylaxis Efficacy for Women using a Preclinical Pharmacokinetic-Pharmacodynamic In Vivo Model.

The efficacy of HIV pre-exposure prophylaxis (PrEP) relies on adherence and may also depend on the route of HIV acquisition. Clinical studies of systemic tenofovir disoproxil fumarate (TDF) PrEP revealed reduced efficacy in women compared to men with similar degrees of adherence. To select the most effective PrEP strategies, preclinical studies are critically needed to establish correlations between drug concentrations (pharmacokinetics [PK]) and protective efficacy (pharmacodynamics [PD]). We utilized an in vivo preclinical model to perform a PK-PD analysis of systemic TDF PrEP for vaginal HIV acquisition. TDF PrEP prevented vaginal HIV acquisition in a dose-dependent manner. PK-PD modeling of tenofovir (TFV) in plasma, female reproductive tract tissue, cervicovaginal lavage fluid and its intracellular metabolite (TFV diphosphate) revealed that TDF PrEP efficacy was best described by plasma TFV levels. When administered at 50 mg/kg, TDF achieved plasma TFV concentrations (370 ng/ml) that closely mimicked those observed in humans and demonstrated the same risk reduction (70%) previously attained in women with high adherence. This PK-PD model mimics the human condition and can be applied to other PrEP approaches and routes of HIV acquisition, accelerating clinical implementation of the most efficacious PrEP strategies.